U.S. patent application number 12/189709 was filed with the patent office on 2009-05-28 for derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators.
This patent application is currently assigned to Valeant Pharmaceuticals International, Inc.. Invention is credited to Huanming Chen, Jianlan Song, Jean-Michel Vernier.
Application Number | 20090137635 12/189709 |
Document ID | / |
Family ID | 40029251 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090137635 |
Kind Code |
A1 |
Vernier; Jean-Michel ; et
al. |
May 28, 2009 |
DERIVATIVES OF 5-AMINO-4,6-DISUBSTITUTED INDOLE AND
5-AMINO-4,6-DISUBSTITUTED INDOLINE AS POTASSIUM CHANNEL
MODULATORS
Abstract
This invention provides compounds of formula I ##STR00001##
where the dashed line represents an optional double bond; where
R.sub.1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl,
imidazolyl, pyrazyl, furyl, thienyl, oxazolyl, isoxazolyl,
thiazolyl, or isothiazolyl, optionally substituted, and other
substituents are defined herein. Such compounds are potassium
channel modulators.
Inventors: |
Vernier; Jean-Michel;
(Laguna Niguel, CA) ; Chen; Huanming; (Irvine,
CA) ; Song; Jianlan; (Cerritos, CA) |
Correspondence
Address: |
McDERMOTT WILL & EMERY LLP
Suite 700, 4370 La Jolla Village Drive
San Diego
CA
92122
US
|
Assignee: |
Valeant Pharmaceuticals
International, Inc.
Aliso Viejo
CA
|
Family ID: |
40029251 |
Appl. No.: |
12/189709 |
Filed: |
August 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60964526 |
Aug 13, 2007 |
|
|
|
Current U.S.
Class: |
514/339 ;
514/419; 546/277.4; 548/495 |
Current CPC
Class: |
C07D 401/06 20130101;
A61P 25/08 20180101; C07D 209/08 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/339 ;
548/495; 514/419; 546/277.4 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 209/20 20060101 C07D209/20; A61K 31/404 20060101
A61K031/404; C07D 401/06 20060101 C07D401/06 |
Claims
1. A compound of formula I ##STR00048## where the dashed line
represents an optional double bond; where R.sub.1 is phenyl,
naphthyl, pyridyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazyl, furyl,
thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl,
optionally substituted with one or two substituents selected
independently from halogen, C.sub.1-C.sub.6 alkyl, mono-halo
C.sub.1-C.sub.6 alkyl, di-halo C.sub.1-C.sub.6 alkyl, CF.sub.3, CN,
S--C.sub.1-C.sub.6 alkyl, or O--C.sub.1-C.sub.6 alkyl; R.sub.2 is
H, methyl, or halogen; R.sub.3 and R.sub.4 are, independently,
CF.sub.3, OCF.sub.3, OC.sub.1-C.sub.3 alkyl, halo or
C.sub.1-C.sub.3 alkyl, where the C.sub.1-C.sub.3 alkyl groups are
optionally substituted with one or more halogen atoms; X.dbd.O or
S; Y is O or S; q=1 or 0; R.sub.5 is C.sub.1-C.sub.6 alkyl where
the C.sub.1-C.sub.6 alkyl alkyl group is optionally substituted
with one or two groups selected, independently, from OH, OMe, OEt,
F, CF.sub.3, Cl, or CN; (CHR.sub.6).sub.wC.sub.3-C.sub.6
cycloalkyl, (CHR.sub.6).sub.wCH.sub.2C.sub.3-C.sub.6 cycloalkyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
CR.sub.6.dbd.CH--C.sub.3-C.sub.6 cycloalkyl,
CH.dbd.CR.sub.6--C.sub.3-C.sub.6 cycloalkyl,
(CHR.sub.6).sub.wC.sub.5-C.sub.6 cycloalkenyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.5-C.sub.6 cycloalkenyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, Ar.sub.1,
(CHR.sub.6).sub.wAr.sub.1, CH.sub.2(CHR.sub.6).sub.wAr.sub.1, or
(CHR.sub.6).sub.wCH.sub.2Ar.sub.1, where w=0-3, Ar.sub.1 is phenyl,
pyridyl, pyrrolyl, thienyl, or furyl, and R.sub.6 is hydrogen,
methyl, halogen, or methoxy; where all cyclic groups are optionally
substituted with one or two substituents selected independently
from C.sub.1-C.sub.3 alkyl, halogen, OH, OMe, SMe, CN, CH.sub.2F,
and trifluoromethyl; or a pharmaceutically acceptable salt, ester,
or hydrate thereof.
2. The compound of claim 1, where R.sub.1 is phenyl, naphthyl,
pyrimidyl, optionally substituted with one or two substituents
selected independently from halogen, C.sub.1-C.sub.4 alkyl,
mono-halo C.sub.1-C.sub.3 alkyl, CF.sub.3, CN, S--CH.sub.3, or
O--C.sub.1-C.sub.3 alkyl; or R.sub.1 is pyrrolyl, furyl, thienyl,
oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, optionally
substituted with halogen, halomethyl, or C.sub.1-C.sub.4 alkyl;
R.sub.2 is H, methyl, or halogen; R.sub.5 is C.sub.3-C.sub.6 alkyl,
(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
(CHR.sub.6).sub.wCH.sub.2C.sub.3-C.sub.6 cycloalkyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
CR.sub.6.dbd.CH--C.sub.3-C.sub.6 cycloalkyl,
CH.dbd.CR.sub.6--C.sub.3-C.sub.6 cycloalkyl,
(CHR.sub.6).sub.wC.sub.5-C.sub.6 cycloalkenyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.5-C.sub.6 cycloalkenyl,
C.sub.2-C.sub.6 alkenyl, Ar.sub.1, (CHR.sub.6).sub.wAr.sub.1,
CH.sub.2(CHR.sub.6).sub.wAr.sub.1, where R.sub.6 is H or methyl;
where w is 1 or 2; and where the C.sub.3-C.sub.6 alkyl group is
optionally substituted with one F or Cl.
3. The compound of claim 2 where R.sub.1 is phenyl, naphthyl, or
pyridyl, optionally substituted with one substituent chosen from
methyl, ethyl, halomethyl, halogen, cyano, SCH.sub.3, methoxy, and
CF.sub.3 and optionally further substituted with halogen or methyl;
or R.sub.1 is thienyl, oxazolyl, or isothiazolyl, optionally
substituted with halogen or C.sub.1-C.sub.4 alkyl; R.sub.2 is H;
R.sub.3 and R.sub.4 are, independently, Cl, CH.sub.3, or methoxy;
and R.sub.5 is C.sub.3-C.sub.6 alkyl,
(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
CR.sub.6.dbd.CH--C.sub.3-C.sub.6 cycloalkyl,
CH.dbd.CR.sub.6--C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6
alkenyl, Ar.sub.1, (CHR.sub.6).sub.wAr.sub.1, or
CH.sub.2(CHR.sub.6).sub.wAr.sub.1.
4. The compound of claim 3, where R.sub.1 is para-halo phenyl or
difluorophenyl.
5. The compound of claim 3, where R.sub.1 is substituted with
methyl or trifluoromethyl.
6. The compound of any of claims 3, 4, or 5, where X is S.
7. The compound of claim 2, which is a compound of formula IA
##STR00049##
8. The compound of claim 2, which is a compound of formula IB
##STR00050##
9. The compound of claim 2, which is a compound of formula IC
##STR00051##
10. The compound of claim 2, which is a compound of formula ID
##STR00052##
11. The compound of any of claims 7, 8, 9, or 10, where R.sub.3 and
R.sub.4 are, independently, methyl, chloro, or methoxy.
12. The compound of any of claims 6, 7, 8, 9, or 10, where R.sub.2
is H and R.sub.3 and R.sub.4 are both methyl.
13. The compound of any of claims 7, 8, 9, or 10, where R.sub.3 and
R.sub.4 are both methyl; R.sub.1 is phenyl, naphthyl, or pyridyl,
optionally substituted with halogen or trifluoromethyl; and R.sub.5
is C.sub.5-C.sub.6 alkyl.
14. A composition comprising a compound of formula I according to
claim 1 and a pharmaceutically acceptable carrier.
15. A composition comprising a pharmaceutically acceptable carrier
and one or more of the following: a compound of formula I according
to claim 1, a pharmaceutically acceptable salt of a compound of
formula I, a pharmaceutically acceptable ester of a compound of
formula I and a pharmaceutically acceptable solvate of a compound
of formula I.
16. A method of preventing or treating a disease or disorder which
is affected by modulation of potassium channels, comprising
administering to a patient in need thereof a therapeutically
effective amount of a composition comprising one or more of the
following: a compound of formula I according to claim 1, a salt of
a compound of formula I and an ester of a compound of formula
I.
17. The compound of claim 7, where R.sub.3 and R.sub.4 are both
methyl, and R.sub.5 is C.sub.5-C.sub.6 alkyl.
18. The compound of claim 17, where R.sub.1 is mono-substituted
phenyl.
19. The compound of claim 18, where R.sub.1 is para fluoro phenyl
or para trifluoromethyl phenyl.
20. The compound of claim 17, where R.sub.1 is 3,5-difluorophenyl
or 3-fluorophenyl.
21. The compound of claim 9, where R.sub.3 and R.sub.4 are both
methyl, and R.sub.5 is C.sub.5-C.sub.6 alkyl.
22. The compound of claim 21, where R.sub.1 is pyridyl or phenyl,
optionally substituted with one additional substituent.
23. The compound of claim 22, where R.sub.1 is para fluoro phenyl
or para trifluoromethyl phenyl.
24. The compound of claim 21, where R.sub.1 is 3,5-difluorophenyl
or 3-fluorophenyl.
25. A composition comprising a compound of formula IA and a
pharmaceutically acceptable carrier.
26. A composition comprising one or more of the following: a
compound of formula IA according to claim 1; a pharmaceutically
acceptable salt of a compound of formula IA; a pharmaceutically
acceptable solvate of a compound of formula IA; a pharmaceutically
acceptable ester of a compound of formula IA.
27. A method of preventing or treating a disease or disorder which
is affected by modulation of voltage-gated potassium channels,
comprising administering to a patient in need thereof a
therapeutically effective amount of a composition, comprising one
or more of the following: a compound of formula IA, a
pharmaceutically acceptable salt of a compound of formula IA, a
pharmaceutically acceptable solvate of a compound of formula IA,
and a pharmaceutically acceptable ester of a compound of formula
IA.
28. A composition comprising a compound of formula IC and a
pharmaceutically acceptable carrier.
29. A composition comprising one or more of the following: a
compound of formula IC according to claim 1; a salt of a compound
of formula IC; a pharmaceutically acceptable salt of a compound of
formula IC; a pharmaceutically acceptable ester of a compound of
formula IC; a pharmaceutically acceptable solvate of a compound of
formula IC.
30. A method of preventing or treating a disease or disorder which
is affected by modulation of voltage-gated potassium channels,
comprising administering to a patient in need thereof a
therapeutically effective amount of a composition comprising one or
more of the following: a compound of formula IC, a pharmaceutically
acceptable salt of a compound of formula IC; a pharmaceutically
acceptable ester of a compound of formula IC; a pharmaceutically
acceptable solvate of a compound of formula IC.
31. A compound which is one of the following:
N-[1-(4-Trifluoromethylbenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-bu-
tyramide
N-[1-(4-Fluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-but-
yramide
N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-buty-
ramide
N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyra-
mide
N-[1-(3,4-Difluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-but-
yramide
N-(4,6-Dimethyl-1-(naphthalen-2-ylmethyl)indolin-5-yl)-3,3-dimethy-
lbutanamide
N-(4,6-Dimethyl-1-(pyridin-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamid-
e
N-(4,6-Dimethyl-1-(pyridin-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutanami-
de
N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimeth-
yl butanamide
N-(4,6-Dimethyl-1-(4-(fluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide
N-(4,6-Dimethyl-1-(3,4-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanam-
ide
N-(4,6-Dimethyl-1-(3,5-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbuta-
namide
N-(4,6-Dimethyl-1-(3-chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutan-
amide and
N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbut-
anamide.
32. A composition comprising a pharmaceutically acceptable carrier
and either a compound chosen from one of the following or a
pharmaceutically acceptable salt, solvate, or ester thereof:
N-[1-(4-Trifluoromethylbenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-bu-
tyramide
N-[1-(4-Fluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-but-
yramide
N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-buty-
ramide
N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyra-
mide
N-[1-(3,4-Difluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-but-
yramide
N-(4,6-Dimethyl-1-(naphthalen-2-ylmethyl)indolin-5-yl)-3,3-dimethy-
lbutanamide
N-(4,6-Dimethyl-1-(pyridin-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamid-
e
N-(4,6-Dimethyl-1-(pyridin-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutanami-
de
N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimeth-
yl butanamide
N-(4,6-Dimethyl-1-(4-(fluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide
N-(4,6-Dimethyl-1-(3,4-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanam-
ide
N-(4,6-Dimethyl-1-(3,5-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbuta-
namide
N-(4,6-Dimethyl-1-(3-chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutan-
amide and
N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbut-
anamide.
33. A method of treating or preventing a disease or condition that
is affected by modulation of potassium channels, comprising
administering to a patient in need thereof a treatment effective
amount of a compound of claim 31.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application No. 60/964,526, filed Aug.
13, 2007, which is incorporated by reference herein in its
entirety.
FIELD OF THE INVENTION
[0002] This invention concerns novel compounds that modulate
potassium channels. The compounds are useful for the treatment and
prevention of diseases and disorders which are affected by
activities of potassium ion channels. One such condition is seizure
disorders.
BACKGROUND OF THE INVENTION
[0003] Epilepsy is a well-known neurological disease, found in
about 3% of the population. Approximately 30% of patients with
epilepsy do not respond to currently available therapies.
Retigabine (N-[2-amino-4-(4-fluorobenzylamino) phenyl]carbamic
acid, ethyl ester] (U.S. Pat. No. 5,384,330) has been found to be
an effective treatment of a broad range of models of seizure
disorders, and it appears to have an unusual mechanism of action.
Bialer, M. et al., Epilepsy Research 1999, 34, 1-41; Wuttke, T. V.,
et al., Mol. Pharmacol. 2005, 67, 1009-1017. Retigabine has also
been found to be useful in treating pain, including neuropathic
pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003, 460,
109-116; Wickenden, A. D. et al., Expert Opin. Ther. Patents, 2004,
14(4).
[0004] "Benign familial neonatal convulsions," an inherited form of
epilepsy, has been associated with mutations in the KCNQ2/3
channels. Biervert, C. et al., Science 1998, 27, 403-06; Singh, N.
A., et al., Nat. Genet. 1998, 18, 25-29; Charlier, C. et al., Nat.
Genet. 1998, 18, 53-55; Rogawski, Trends in Neurosciences 2000, 23,
393-398. Subsequent investigations have established that one
important site of action of retigabine is the KCNQ2/3 channel.
Wickenden, A. D. et al., Mol. Pharmacol. 2000, 58,591-600; Main, M.
J. et al., Mol. Pharmacol. 2000, 58, 253-62. Retigabine has been
shown to increase the conductance of the channels at the resting
membrane potential, with a possible mechanism involving binding of
the activation gate of the KCNQ 2/3 channel. Wuttke, T. V., et al.,
Mol. Pharmacol. 2005, op. cit. With increased sophistication of
research in this area, retigabine has also been shown to increase
neuronal M currents and to increase the channel open probability of
KCNQ 2/3 channels. Delmas, P. and Brown, D. A. Nat. Revs Neurosci.,
vol. 6, 2005, 850-62; Tatulian, L. and Brown, D. A., J. Physiol.,
(2003) 549, 57-63.
[0005] The most therapy-resistant type of seizure is the so-called
"complex partial seizure." Retigabine has been found to be
particularly potent in models for drug-refractory epilepsy.
Retigabine is also active in several other seizure models. Because
of retigabine's broad spectrum of activity and unusual molecular
mechanism, there is hope that retigabine will be effective in
management of several seizure types, including the complex partial
seizure, and in treatment of hitherto untreatable forms of
epilepsy. Porter, Roger J., Nohria, Virinder, and Rundfeldt, Chris,
Neurotherapeutics, 2007, vol. 4, 149-154.
[0006] The recognition of retigabine as a potassium channel
modulator has inspired a search for other--and, hopefully,
better--potassium channel modulators among compounds with
structural features similar to those of retigabine.
BRIEF DESCRIPTION OF THE INVENTION
[0007] In one embodiment, this invention provides a compound of
formula I
##STR00002##
where the dashed line represents an optional double bond; where
R.sub.1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl,
imidazolyl, pyrazyl, furyl, thienyl, oxazolyl, isoxazolyl,
thiazolyl, or isothiazolyl, optionally substituted with one or two
substituents selected independently from halogen, C.sub.1-C.sub.6
alkyl, mono-halo C.sub.1-C.sub.6 alkyl, di-halo C.sub.1-C.sub.6
alkyl, CF.sub.3, CN, S--C.sub.1-C.sub.6 alkyl, or
O--C.sub.1-C.sub.6 alkyl; R.sub.2 is H, methyl, or halogen; R.sub.3
and R.sub.4 are, independently, CF.sub.3, OCF.sub.3,
OC.sub.1-C.sub.3 alkyl, halo or C.sub.1-C.sub.3 alkyl, where the
C.sub.1-C.sub.3 alkyl groups are optionally substituted with one or
more halogen atoms; X.dbd.O or S; Y is O or S; q=1 or 0; R.sub.5 is
C.sub.1-C.sub.6 alkyl where the C.sub.1-C.sub.6 alkyl alkyl group
is optionally substituted with one or two groups selected,
independently, from OH, OMe, OEt, F, CF.sub.3, Cl, or CN;
(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
(CHR.sub.6).sub.wCH.sub.2C.sub.3-C.sub.6 cycloalkyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
CR.sub.6.dbd.CH--C.sub.3-C.sub.6 cycloalkyl,
CH.dbd.CR.sub.6--C.sub.3-C.sub.6 cycloalkyl,
(CHR.sub.6).sub.wC.sub.5-C.sub.6 cycloalkenyl,
CH.sub.2(CHR.sub.6).sub.wC.sub.5-C.sub.6 cycloalkenyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, Ar.sub.1,
(CHR.sub.6).sub.wAr.sub.1, CH.sub.2(CHR.sub.6).sub.wAr.sub.1, or
(CHR.sub.6).sub.wCH.sub.2Ar.sub.1, where w=0-3, Ar.sub.1 is phenyl,
pyridyl, pyrrolyl, thienyl, or furyl, and R.sub.6 is hydrogen,
methyl, halogen, or methoxy; where all cyclic groups are optionally
substituted with one or two substituents selected independently
from C.sub.1-C.sub.3 alkyl, halogen, OH, OMe, SMe, CN, CH.sub.2F,
and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
Such compounds are potassium channel modulators.
[0008] In another embodiment, this invention provides a composition
comprising a pharmaceutically acceptable carrier and one or more of
the following: a pharmaceutically effective amount of a compound of
formula I; a pharmaceutically effective amount of a
pharmaceutically acceptable salt thereof; a pharmaceutically
effective amount of a pharmaceutically acceptable ester
thereof.
[0009] In yet another embodiment, this invention provides a method
of preventing or treating a disease or disorder which is affected
by modulation of voltage-gated potassium channels, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of formula I or a salt or ester
thereof.
[0010] In another embodiment, this invention provides or
contemplates a composition comprising a pharmaceutically acceptable
carrier and at least one of the following: i) a pharmaceutically
effective amount of a compound of formula I; ii) a pharmaceutically
acceptable salt thereof; iii) a pharmaceutically acceptable ester
thereof; iv) a pharmaceutically acceptable solvate thereof.
[0011] In another embodiment, this invention provides or
contemplates a method of treating or preventing a disease or
disorder which is affected by enhancement of neural M currents
comprising administering to a patient in need thereof one or more
of the following: i) a pharmaceutically effective amount of a
compound of formula I; ii) a pharmaceutically acceptable salt
thereof; iii) a pharmaceutically acceptable ester thereof; iv) and
a pharmaceutically acceptable solvate thereof.
[0012] In yet another embodiment, this invention provides a method
of preventing or treating a disease or disorder which is affected
by activation of voltage-gated potassium channels, comprising
administering to a patient in need thereof one or more of the
following: a pharmaceutically effective amount of a compound of
formula I; ii) a pharmaceutically acceptable salt thereof; iii) a
pharmaceutically acceptable ester thereof; and iv) a
pharmaceutically acceptable solvate thereof.
[0013] In yet another embodiment, this invention provides or
contemplates a method of treating or preventing a seizure disorder
in a human comprising administering to a patient afflicted or
potentially afflicted with such disorder one or more of the
following: a pharmaceutically effective amount of a compound of
formula I; ii) a pharmaceutically acceptable salt thereof; iii) a
pharmaceutically acceptable ester thereof; iv) and a
pharmaceutically acceptable solvate thereof.
[0014] In another embodiment, this invention provides or
contemplates a pharmaceutical formulation for oral administration
comprising a therapeutically effective amount of a compound of
formula I and either an appropriate tabletting agent or an
appropriate syrup for pediatric use.
[0015] In another embodiment, this invention provides or
contemplates a tablet for oral administration comprising a
therapeutically effective amount of a compound of formula I and an
appropriate tabletting agent.
[0016] In another appropriate embodiment, this invention provides
or contemplates a syrup for pediatric use comprising a solution or
dispersion or suspension of a compound of formula I and an
appropriate syrup.
[0017] In another embodiment, this invention contemplates a
pharmaceutical formulation for administration to animals, including
companion animals (dogs and cats), and livestock comprising a
therapeutically effective amount of a compound of formula I and a
veterinary acceptable carrier.
[0018] In another embodiment, this invention contemplates a method
of preventing or treating a disease or disorder which is affected
by activation of voltage-gated potassium channels comprising
administering to an animal in need thereof one or more of the
following: i) a pharmaceutically effective amount of a compound of
formula I; ii) a pharmaceutically acceptable salt thereof; iii) a
pharmaceutically acceptable ester thereof; iv) and a
pharmaceutically acceptable solvate thereof.
[0019] In another embodiment, this invention contemplates a method
of treating a seizure disorder in an animal comprising
administering to an animal afflicted or potentially afflicted with
such a disorder one or more of the following: i) a pharmaceutically
effective amount of a compound of formula I; ii) a pharmaceutically
acceptable salt thereof; iii) a pharmaceutically acceptable ester
thereof; iv) and a pharmaceutically acceptable solvate thereof.
[0020] This invention includes all tautomers, salts, and
stereoisomeric forms of compounds of formula I. This invention also
includes all compounds of this invention where one or more atoms
are replaced by a radioactive isotope thereof.
[0021] This invention provides or contemplates compounds of formula
I above where NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is each of the
following: NHC(.dbd.O)R.sub.5, NHC(.dbd.O)OR.sub.5,
NHC(.dbd.S)R.sub.5, NHC(.dbd.S)SR.sub.5, NHC(.dbd.S)OR.sub.5, and
NHC(.dbd.O)SR.sub.5.
[0022] Thus, in one embodiment, this invention provides or
contemplates a compound of formula I, where
NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is NHC(.dbd.O)R.sub.5.
[0023] In another embodiment, this invention provides or
contemplates a compound of formula I, where
NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is NHC(.dbd.S)R.sub.5.
[0024] In another embodiment, this invention provides or
contemplates a compound of formula I, where
NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is NHC(.dbd.S)SR.sub.5.
[0025] In another embodiment, this invention provides or
contemplates a compound of formula I, where
NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is each NHC(.dbd.O)OR.sub.5.
[0026] In another embodiment, this invention provides or
contemplates a compound of formula I, where
NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is NHC(.dbd.S)OR.sub.5.
[0027] In another embodiment, this invention provides or
contemplates a compound of formula I, where
NH--C(.dbd.X)--(Y).sub.q--R.sub.5 is NHC(.dbd.O)SR.sub.5.
[0028] In a more specific embodiment, this invention provides or
contemplates a compound of formula I, where R.sub.5 is
C.sub.1-C.sub.6 alkyl, (CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl,
(CHR.sub.6).sub.wCH.sub.2C.sub.3-C.sub.6 cycloalkyl, or
CH.sub.2(CHR.sub.6).sub.wC.sub.3-C.sub.6 cycloalkyl.
[0029] In a still more specific embodiment, this invention provides
or contemplates a compound of formula I, where R.sub.5 is
C.sub.5-C.sub.6 alkyl, (CH.sub.2).sub.wC.sub.5-C.sub.6 cycloalkyl,
or (CHR.sub.6).sub.wCH.sub.2C.sub.5-C.sub.6 cycloalkyl.
[0030] In another more specific embodiment, this invention provides
or contemplates a compound of formula I, where R.sub.5 is
C.sub.5-C.sub.6 alkyl, optionally substituted with one or two OH
groups.
[0031] In another subgeneric embodiment, this invention provides or
contemplates a compound of formula IA below.
##STR00003##
[0032] In another subgeneric embodiment, this invention provides or
contemplates a compound of formula IB below.
##STR00004##
[0033] In another subgeneric embodiment, this invention provides or
contemplates a compound of formula IC below.
##STR00005##
[0034] In another subgeneric embodiment, this invention provides or
contemplates a compound of formula ID below.
##STR00006##
[0035] In another subgeneric embodiment, this invention provides or
contemplates a compound of formula IA, IB, IC, or ID, where R.sub.3
and R.sub.4 are, independently, methyl, chloro, or methoxy.
[0036] In another, more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.3 and R.sub.4 are both methyl.
[0037] In another more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is phenyl, substituted with halogen,
cyano, CF.sub.3, or methoxy, R.sub.2 is H or methyl, and R.sub.5 is
C.sub.5-C.sub.6 alkyl or CH.sub.2--C.sub.3-C.sub.6 cycloalkyl.
[0038] In another more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is substituted phenyl or unsubstituted
phenyl.
[0039] In another more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is phenyl, substituted with halogen.
[0040] In a still more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is fluorophenyl, or difluorophenyl.
[0041] In another more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is phenyl, substituted with
trifluoromethyl.
[0042] In another more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is halophenyl, and R.sub.5 is
C.sub.5-C.sub.6 alkyl or CH.sub.2--C.sub.5-C.sub.6 cycloalkyl.
[0043] In another more specific subgeneric embodiment, this
invention provides or contemplates a compound of formula IA, IB,
IC, or ID, where R.sub.1 is halophenyl and R.sub.5 is
CH.sub.2--C.sub.4-alkyl or CH.sub.2--C.sub.5-- alkyl.
[0044] In another more specific embodiment, this invention provides
or contemplates a compound of formula IA, IB, IC, or ID, where
R.sub.1 is halo pyridyl.
[0045] In another more specific embodiment, this invention provides
or contemplates a compound of formula IA or IC, where R.sub.1 is
dihalophenyl or dihalopyridyl; R.sub.2 is H; and R.sub.3 and
R.sub.4 are C.sub.1, CF.sub.3, or CH.sub.3.
[0046] In another more specific embodiment, this invention provides
or contemplates a compound of formula IB or ID, where R.sub.1 is
dihalophenyl or dihalopyridyl; R.sub.2 is H; and R.sub.3 and
R.sub.4 are C.sub.1, CF.sub.3, or CH.sub.3.
[0047] In another more specific embodiment, this invention provides
or contemplates a compound of formula IB or ID, where R.sub.1 is
halophenyl or halopyridyl; R.sub.2 is H; and R.sub.3 and R.sub.4
are C.sub.1, CF.sub.3, or CH.sub.3.
[0048] In another more specific embodiment, this invention provides
or contemplates a compound of formula IA or IC, where R.sub.1 is
3,5-dichlorophenyl or 3,5-difluorophenyl.
[0049] In another more specific embodiment, this invention provides
or contemplates a compound of formula IB or ID, where R.sub.1 is
3,5-dichlorophenyl or 3,5-difluorophenyl.
[0050] In another embodiment, this invention provides or
contemplates a compound of formula I, in which R.sub.5 is
C.sub.1-C.sub.6 alkyl, where the C.sub.1-C.sub.6 alkyl group is
substituted with one or two groups selected, independently, from
OH, OMe, OEt, F, CF.sub.3, Cl, or CN.
[0051] In another embodiment, this invention provides or
contemplates a compound of formula I, in which X is S, q is zero,
R.sub.1 is substituted phenyl, R.sub.2 is H, and R.sub.5 is
C.sub.1-C.sub.6 alkyl.
[0052] In another embodiment, this invention provides or
contemplates a compound of formula I, in which X is S, q is zero,
R.sub.1 is substituted phenyl, R.sub.2 is H, and R.sub.5 is
C.sub.1-C.sub.6 alkyl.
[0053] In yet another embodiment, this invention provides or
contemplates a compound of formula I, in which X is S, q is 1, Y is
O, R.sub.1 is substituted phenyl, R.sub.2 is H, and R.sub.5 is
C.sub.1-C.sub.6 alkyl.
[0054] In yet another embodiment, this invention provides or
contemplates a compound of formula I, in which X is S, q is 1, Y is
S, R.sub.1 is substituted phenyl, R.sub.2 is H, and R.sub.5 is
C.sub.1-C.sub.6 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0055] In designing compounds with therapeutic properties superior
to those of retigabine, shown below,
##STR00007##
and in optimizing the desirable therapeutic properties of this
compound, the present inventors have discovered that compounds of
formula I have surprising and exceptional activity toward potassium
channels, as evidenced by potent activity, as measured in the
rubidium (Rb+) efflux assay described below.
[0056] The inventors have further discovered that substitution at
both the 2- and 6-positions of the central benzene ring confers a
number of desirable properties, including both increased potency
and increased stability in vivo. Thus, 2,6-di-substitution is a
critical feature of some embodiments of this invention.
[0057] The inventors have further discovered that, in particular,
alkyl substitution at both the 2- and 6-positions of the central
benzene ring confers desirable properties, including both increased
potency and increased stability in vivo. Thus, 2,6-dimethyl
substitution is a critical feature of one embodiment of this
invention.
[0058] Moreover, the inventors have also discovered that
substitution with alkoxide groups at both the 2- and 6-positions of
the central benzene ring also confers a number of desirable
properties, including both increased potency and increased
stability in vivo. Thus, such substitution is a critical feature of
another embodiment of this invention.
[0059] Moreover, the inventors have also discovered that
substitution at the 2- and 6-positions of the central benzene ring
with substituents chosen from halogen, trifluoromethyl, and methoxy
also confers a number of desirable properties, including both
increased potency and increased stability in vivo. Thus, such
substitution is a critical feature of yet another embodiment of
this invention.
[0060] Among the embodiments of this invention, the most active
compounds display a 40- to 400-fold improvement over retigabine,
with the most promising compounds displaying EC.sub.50s in the
single-digit nanomolar range. Activities of several compounds of
this invention are shown in Table 1 below. The activity of
retigabine is shown for comparative purposes.
[0061] As used herein the term "potassium channel modulator" refers
to a compound capable of causing an increase in potassium channel
currents. It also refers to a compound capable of increasing the
KCNQ2/3 channel open probability. For preliminary testing of
compounds for potassium channel modulating ability, the inventors
have employed the rubidium ion efflux test described below.
[0062] As contemplated by this invention, compounds of formula I
are designed for oral or intravenous dosing of up to approximately
2000 mg per day. Thus, this invention contemplates solutions and
suspensions of compounds of formula I formulated for intravenous
administration. Similarly, solutions and suspensions comprising a
syrup such as sorbitol or propylene glycol, among many other
examples, in addition to compounds of formula I, suitable for oral
pediatric administration, are also contemplated. Additionally, both
chewable and non-chewable tablets comprising compounds of formula
I, along with pharmaceutically acceptable tabletting agents and
other pharmaceutically acceptable carriers and excipients, are also
contemplated.
[0063] As used herein, the term "pharmaceutically acceptable
carrier" comprises such excipients, binders, lubricants, tabletting
agents and disintegrants as are typically used in the art of
formulation of pharmaceuticals. Examples of such agents
include--but are not limited to--microcrystalline cellulose,
lactose, starch, and dicalcium phosphate, and Providone. However,
in view of the incompatibility of primary amines with lactose, this
invention does not contemplate compositions in which active
ingredients with primary amine groups are combined with lactose.
Additionally, disintegrants such as sodium starch glycolate,
lubricants such as stearic acid and SiO.sub.2, and solubility
enhancers such as cyclodextrins, among many other examples for each
group, are contemplated. Such materials and the methods of using
them are well known in the pharmaceutical art. Additional examples
are provided in Kibbe, Handbook of Pharmaceutical Excipients,
London, Pharmaceutical Press, 2000.
[0064] The invention also contemplates pharmaceutical formulations
for administration to animals, comprising a therapeutically
effective amount of a compound of formula I and a veterinary
acceptable carrier. Any animal that is susceptible to seizure
disorders is included within the scope of this invention.
Synthetic Procedures
[0065] Section I. Preparation of compounds of formula XIV is
outlined in Scheme 1.
##STR00008## ##STR00009##
[0066] Section II. Preparation of compounds of formula IX is
outlined in Scheme 2.
##STR00010##
[0067] Section III. Preparation of compounds of formula XIX is
outlined in Scheme 3.
##STR00011##
[0068] Section IV. Preparation of compounds of formula XX is
outlined in Scheme 4.
##STR00012##
[0069] Section V. Preparation of compounds of formula XXI is
outlined in Scheme 5.
##STR00013##
[0070] Section VI. Preparation of compounds of formula XXII is
outlined in Scheme 6.
##STR00014##
[0071] Section VII. Preparation of compounds of formula XXIII is
outlined in Scheme 7.
##STR00015##
[0072] Section VIII. Preparation of compounds of formula XXIV is
outlined in Scheme 8.
##STR00016##
[0073] Section IX. Preparation of compounds of formula XXVI is
outlined in Scheme 9.
##STR00017##
[0074] Section X. Preparation of compounds of formula XXVII is
outlined in Scheme 10.
##STR00018##
4,6-Dimethyl-1H-indole-2-carboxylic acid ethyl ester (2)
[0075] In a flask fitted with a Dean-Stark trap, p-toluenesulfonic
acid monohydrate (132 g, 0.69 mol) in 500 ml of benzene was heated
at reflux for 2 hours. A solution of 3,5-dimethylphenylhydrazine
hydrochloride (34.5 g, 0.2 mol), ethyl pyruvate (23.2 g, 0.2 mol),
and p-toluenesulfonic acid monohydrate (0.85 g, 0.005 mol) in 500
ml of benzene, which had been refluxed for 2 hours with water
removed through a Dean-Stark apparatus was then added. The
resulting mixture was heated at reflux and stirred overnight. After
cooling, the solution was treated with saturated sodium bicarbonate
solution and diluted with methylene chloride. The organic portion
was washed twice with saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by ISCO (hexane/EtOAc, 0-30%, 40
min) to give yellow solids, which was recrystallized from
hexane/ethyl acetate (10%) to give colorless needles (35.6 g, 82%).
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 11.68 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.12 (s, 1H), 7.05 (s, 1H), 6.71
(s, 1H), 4.33 (q, J=6.8 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.34
(t, J=6.8 Hz, 3H).
4,6-Dimethyl-1H-indole-2-carboxylic acid (3)
[0076] A mixture of 4,6-dimethyl-1H-indole-2-carboxylic acid ethyl
ester (22 g, 0.1 mol) and lithium hydroxide (4.8 g, 0.2 mol) in 400
ml of ethanol was heated at reflux overnight. The solvent was
removed under reduced pressure and the residue was dissolved in
water and neutralized with 10% HCl to pH<3. The resulting
precipitates were filtered and washed with water and dried in vacuo
at 40.degree. C. to give white solids (18 g, 95%). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 12.73 (brs, 1H, exchangeable with
D.sub.2O, NH), 11.55 (brs, 1H, exchangeable with D.sub.2O, NH),
7.06 (s, 1H), 7.03 (s, 1H), 6.69 (s, 1H), 2.44 (s, 3H), 2.35 (s,
3H).
4,6-Dimethyl-1H-indole (4)
[0077] Method A: A mixture of 4,6-dimethyl-1H-indole-2-carboxylic
acid (3.61 g, 19.09 mmol, 1 equiv), copper powder (850 mg, 13.36
mmol, 0.7 equiv), and freshly distilled quinoline (50 mL) were
brought at reflux for 2 h. The mixture was then cooled and filtered
on Celite. The filtrate was poured on ice, and the solution was
brought to pH 4 with concentrated HCl and extracted with ethyl
acetate (3.times.100 ml). The combined extracts were washed with 2
N HCl (3.times.100 mL), saturated NaHCO.sub.3, and brine. The
organic solution was dried over MgSO.sub.4 and concentrated. The
residue was flash chromatographed on silica gel using hexane-AcOEt
(85-15) to give a white solid (2.6 g, 94%). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 10.8 (brs, 1H, exchangeable with
D.sub.2O, NH), 7.19 (t, J=2 Hz, 1H), 6.99 (s, 1H), 6.62 (s, 1H),
6.36 (t, J=2 Hz, 1H), 2.41 (s, 3H), 2.34 (s, 3H).
[0078] Method 2: This indole also was prepared heating 26 g (0.14
mol) of 4,6-dimethyl-1H-indole-2-carboxylic acid to 230.degree. C.
for 3 hours. After cooling, the reactant was distilled under
reduced pressure (2.9-4.4 mmHg) at 130-135.degree. C. to give a
pure product as colorless oil (15.6 g, 77%).
[0079] 4,6-Dimethylindoline (5) and 1-Acetyl-4,6-dimethylindoline
(6) are prepared by the following procedure.
[0080] 4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20
ml), and sodium cyanoborohydride (2.3 g) was added portionwise at
15.degree. C. The mixture was stirred at said temperature for one
hour and poured into ice water. Saturated aqueous sodium
bicarbonate was added to neutralize the mixture and the mixture was
extracted with ethyl acetate. The extract was washed with saturated
brine and dried over sodium sulfate. The solvent was evaporated
under reduced pressure. The residue was dissolved in benzene, and
acetic anhydride (840 mg) was added, which was followed by stirring
at room temperature for one hour. The reaction mixture was washed
with saturated aqueous sodium bicarbonate and saturated brine, and
dried over sodium sulfate. The solvent was evaporated under reduced
pressure. The residue was chromatographed (ISCO, hexane/EtOAc,
0-40%, 40 min) to give 1.3 g of 1-acetyl-4,6-dimethylindoline.
[0081] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.18 (6H, s), 2.30 (3H,
s), 3.00 (2H, t, J=8.3 Hz), 4.03 (2H, t, J=8.3 Hz), 6.66 (1H, s),
7.89 (1H, s).
[0082] 1-Acetyl-4,6-dimethyl-5-nitroindoline (7) was prepared as
follows.
[0083] 1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in
acetic anhydride (35 ml), and nitric acid (d=1.5, 0.92 ml)
dissolved in acetic anhydride (15 ml) was added dropwise at
0.degree. C. The mixture was stirred at room temperature for one
hour and poured into ice water. Saturated aqueous sodium
bicarbonate was added to neutralize the mixture, and the mixture
was extracted with chloroform. The extract was washed with
saturated brine and dried over sodium sulfate. The solvent was
evaporated under reduced pressure. The residue was chromatographed
(ISCO, hexane/EtOAc, 0-40%, 40 min) to give 2.4 g of white solids.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 6.95 (s, 1H), 4.19 (t,
J=8.0 Hz, 2H), 3.04 (t, J=8.0 Hz, 2H), 2.26 (s, 3H), 2.23 (s, 3H),
2.18 (s, 3H).
[0084] 4,6-Dimethyl-5-nitroindoline (8) was prepared by the
following procedure.
[0085] 1-Acetyl-4,6-dimethyl-5-nitroindoline (2.4 g) was dissolved
in methanol (25 ml). Hydrochloric acid 6N (20 ml) was added,
followed by reflux for 15 hours. After the completion of the
reaction, the solvent was evaporated under reduced pressure. The
residue was dissolved in chloroform, and the mixture was washed
with saturated aqueous sodium bicarbonate and saturated brine, and
dried over sodium sulfate. The solvent was evaporated under reduced
pressure. The residue was chromatographed (ISCO, hexane/EtOAc,
0-40%, 40 min) to give 1.8 g of 4,6-dimethyl-5-nitroindoline as
yellow solids. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 6.36
(brs, 1H, exchangeable with D.sub.2O, NH), 6.20 (s, 1H), 3.54 (t,
J=8.0 Hz, 2H), 2.91 (t, J=8.0 Hz, 2H), 2.17 (s, 3H), 2.10 (s,
3H).
4,6-Dimethyl-5-nitro-1-(4-trifluoromethyl-benzyl)-indoline (9):
R=CF.sub.3
[0086] 4,6-dimethyl-5-nitroindoline (0.33 g, 1.7 mmol) was
dissolved in dimethylformamide (10 ml), and sodium hydride (ca. 60%
in oil suspension, 136 mg) was added at 0.degree. C. The mixture
was stirred at 0.degree. C. for 0.5 hour and
4-trifluoromethylbenzyl bromide (0.48 g, 2 mmol)) was added to the
reaction mixture, which was followed by stirring at room
temperature overnight. Water was added to the reaction mixture, and
the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine and dried over sodium sulfate. The
solvent was evaporated under reduced pressure. The residue was
chromatographed (ISCO, hexane/EtOAc, 0-40%, 40 min) to give yellow
solids (0.55 g, 92%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
7.73 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 6.41 (s, 1H), 4.52
(s, 2H), 3.50 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 2.20 (s,
3H), 2.11 (s, 3H).
[0087] The following compounds were prepared by the above
procedure: [0088] 4,6-Dimethyl-5-nitro-1-(4-fluorobenzyl)-indoline
[0089] 4,6-Dimethyl-5-nitro-1-(3-chlorobenzyl)-indoline [0090]
4,6-Dimethyl-5-nitro-1-(4-bromobenzyl)-indoline [0091]
4,6-Dimethyl-5-nitro-1-(3,4-difluorobenzyl)-indoline [0092]
4,6-Dimethyl-5-nitro-1-(naphthalen-2-ylmethyl)-indoline [0093]
4,6-Dimethyl-5-nitro-1-(pyridin-4-ylmethyl)-indoline [0094]
4,6-Dimethyl-5-nitro-1-(pyridin-3-ylmethyl)-indoline
4,6-Dimethyl-5-nitro-1-(4-(trifluoromethyl)benzyl)-1H-indole (12):
R=CF.sub.3
[0095] A solution of
4,6-dimethyl-5-nitro-1-(4-trifluoromethyl-benzyl)-indoline (350 mg,
1 mmol) and DDQ (454 mg, 2 mmol) in 30 ml of anhydrous dioxane was
stirred a 50.degree. C. for 2 days. After cooling, the solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (ISCO, hexane/EtOAc, 0-40%, 40
min) to give yellow crystals (300 mg, 86%).
[0096] The following compounds were prepared by the above
procedure. [0097] 4,6-Dimethyl-5-nitro-1-(4-fluorobenzyl)-1H-indole
[0098] 4,6-Dimethyl-5-nitro-1-(4-chlorobenzyl)-1H-indole [0099]
4,6-Dimethyl-5-nitro-1-(4-bromobenzyl)-1H-indole [0100]
4,6-Dimethyl-5-nitro-1-(3,4-difluorobenzyl)-1H-indole [0101]
4,6-Dimethyl-5-nitro-1-(3,5-difluorobenzyl)-1H-indole
1-(4-Trifluoromethyl-benzyl)-4,6-dimethyl-5-aminoindoline (10):
R=CF.sub.3
[0102] 1-(4-Trifluoromethyl-benzyl)-4,6-dimethyl-5-nitroindoline
(1.0 g) was dissolved in methanol (40 ml) and catalytic amount of
Raney Ni was added to allow hydrogenation at room temperature under
regular pressure. After the completion of the reaction, catalyst
was filtered off, and the filtrate was evaporated under reduced
pressure to give the white solid product, which is pure enough for
next step without further purification.
[0103] The following compounds were prepared by the above
procedure: [0104] 1-(4-Fluorobenzyl)-4,6-dimethyl-5-amino indo line
[0105] 1-(3-Chlorobenzyl)-4,6-dimethyl-5-amino indo line [0106]
1-(4-Bromobenzyl)-4,6-dimethyl-5-amino indo line [0107]
1-(3,4-Difluorobenzyl)-4,6-dimethyl-5-aminoindoline [0108]
1-(Naphthalen-2-ylmethyl)-4,6-dimethyl-5-amino indo line [0109]
1-(Pyridin-4-ylmethyl)-4,6-dimethyl-5-amino indo line [0110]
1-(Pyridin-3-ylmethyl)-4,6-dimethyl-5-amino indo line [0111]
4,6-Dimethyl-5-amino-1-(4-(trifluoromethyl)benzyl)-1H-indole [0112]
4,6-Dimethyl-5-amino-1-(4-fluorobenzyl)-1H-indole [0113]
4,6-Dimethyl-5-amino-1-(4-chlorobenzyl)-1H-indole [0114]
4,6-Dimethyl-5-amino-1-(4-bromobenzyl)-1H-indole [0115]
4,6-Dimethyl-5-amino-1-(3,4-difluorobenzyl)-1H-indole [0116]
4,6-Dimethyl-5-amino-1-(3,5-difluorobenzyl)-1H-indole
N-[1-(4-Trifluoromethyl-benzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-bu-
tyramide (11): R=CF.sub.3
##STR00019##
[0118] To a solution of
5-amino-4,6-dimethyl-1-(4-trifluoromethylbenzyl)indoline (0.26 g,
0.82 mmol) from above and triethylamine (125 mg, 1.24 mmol) in
anhydrous methylene chloride (20 ml) was added dropwise tert-butyl
acetyl chloride (135 mg, 1 mmol) at 0.degree. C. The reaction
mixture was stirred at room temperature for 18 hours. Water was
added to the reaction mixture, and the mixture was washed with
saturated brine and dried over sodium sulfate. The solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (ISCO, hexane/EtOAc, 0-40%, 40
min) and recrystallized from hexane/EtOAc (5:1) to give 290 mg
(85%) of the white solids. .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
.delta. 8.80 (brs, 1H, exchangeable with D.sub.2O, NH), 7.72 (d,
J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 6.29 (s, 1H), 4.34 (s, 2H),
3.28 (t, J=8.0 Hz, 2H), 2.82 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03
(s, 3H), 1.96 (s, 3H), 1.07 (s, 9H). MS: 419 (M+1).
[0119] The following compounds were prepared by the above
procedure.
N-[1-(4-Fluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
##STR00020##
[0121] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.78 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.37 (dd, J=8.8 and 5.7 Hz, 2H),
7.16 (t, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.22 (s, 2H), 3.22 (t, J=8.0
Hz, 2H), 2.79 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.95
(s, 3H), 1.05 (s, 9H). MS: 369 (M+1).
N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
##STR00021##
[0123] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.79 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.34 (m, 4H), 6.29 (s, 1H), 4.25
(s, 2H), 3.26 (t, J=8.0 Hz, 2H), 2.81 (t, J=8.0 Hz, 2H), 2.17 (s,
2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.05 (s, 9H). MS: 385 (M+1).
N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide
##STR00022##
[0125] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.78 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.54 (d, J=8.0 Hz, 2H), 7.30 (d,
J=8.0 Hz, 2H), 6.29 (s, 1H), 4.21 (s, 2H), 3.24 (t, J=8.0 Hz, 2H),
2.80 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.02 (s, 3H), 1.95 (s, 3H),
1.05 (s, 9H). MS: 429 (M+1).
N-[1-(3,4-Difluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyrami-
de
##STR00023##
[0127] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.79 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.41 (m, 2H), 7.19 (m, 1H), 6.30
(s, 1H), 4.22 (s, 2H), 3.25 (t, J=8.0 Hz, 2H), 2.80 (t, J=8.0 Hz,
2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.05 (s, 9H). MS:
387 (M+1).
N-(4,6-Dimethyl-1-(naphthalen-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutanam-
ide
##STR00024##
[0129] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.79 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.89 (m, 4H), 7.50 (m, 3H), 6.35
(s, 1H), 4.39 (s, 2H), 3.29 (t, J=8.0 Hz, 2H), 2.84 (t, J=8.0 Hz,
2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.97 (s, 3H), 1.05 (s, 9H). MS:
401 (M+1).
N-(4,6-Dimethyl-1-(pyridin-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide
##STR00025##
[0131] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.80 (brs, 1H,
exchangeable with D.sub.2O, NH), 8.52 (d, J=8.0 Hz, 2H), 7.34 (d,
J=8.0 Hz, 2H), 6.25 (s, 1H), 4.28 (s, 2H), 3.30 (t, J=8.0 Hz, 2H),
2.84 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.02 (s, 3H), 1.97 (s, 3H),
1.05 (s, 9H). MS: 352 (M+1).
N-(4,6-Dimethyl-1-(pyridin-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide
##STR00026##
[0133] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.79 (brs, 1H,
exchangeable with D.sub.2O, NH), 8.57 (d, J=2.0 Hz, 1H), 8.49 (dd,
J=2.0 and 4.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0 and
4.4 Hz, 1H), 6.36 (s, 1H), 4.27 (s, 2H), 3.24 (t, J=8.0 Hz, 2H),
2.79 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.04 (s, 3H), 1.95 (s, 3H),
1.05 (s, 9H). MS: 352 (M+1).
N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethylb-
utanamide
##STR00027##
[0135] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 9.00 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.67 (d, J=8.0 Hz, 2H), 7.41 (d,
J=3.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.09 (s, 1H), 6.50 (d, J=3.2
Hz, 1H), 5.50 (s, 2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.19 (s, 3H),
1.07 (s, 9H). MS: 417 (M+1).
N-(4,6-Dimethyl-1-(4-(fluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide
##STR00028##
[0137] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.99 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.39 (d, J=3.2 Hz, 1H), 7.21 (dd,
J=8.8 and 5.7 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 7.12 (s, 1H), 6.46
(d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.22 (s, 3H), 2.20
(s, 3H), 1.07 (s, 9H). MS: 367 (M+1).
N-(4,6-Dimethyl-1-(3,4-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanami-
de
##STR00029##
[0139] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 9.00 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.41 (d, J=3.2 Hz, 1H), 7.35 (m,
1H), 7.23 (m, 1H), 7.14 (s, 1H), 6.95 (m, 1H), 6.48 (d, J=3.2 Hz,
1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 1.07
(s, 9H). MS: 385 (M+1).
N-(4,6-Dimethyl-1-(3,5-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanami-
de
##STR00030##
[0141] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 9.01 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.43 (d, J=3.2 Hz, 1H), 7.13 (s,
1H), 7.10 (m, 1H), 6.81 (m, 2H), 6.49 (d, J=3.2 Hz, 1H), 5.40 (s,
2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.21 (s, 3H), 1.08 (s, 9H). MS:
385 (M+1).
N-(4,6-Dimethyl-1-(3-chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide
##STR00031##
[0143] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 9.00 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.41 (d, J=3.2 Hz, 1H), 7.31 (m,
2H), 7.19 (s, 1H), 7.12 (s, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.49
(d, J=3.2 Hz, 1H), 5.39 (s, 2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.20
(s, 3H), 1.08 (s, 9H). MS: 383 (M+1).
N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide
##STR00032##
[0145] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.99 (brs, 1H,
exchangeable with D.sub.2O, NH), 7.49 (d, J=8.4 Hz, 2H), 7.38 (d,
J=3.2 Hz, 1H), 7.08 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.47 (d, J=3.2
Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.19 (s, 3H), 2.17 (s, 3H),
1.07 (s, 9H). MS: 427 (M+1).
Biological Results
[0146] Compounds of this invention formula were evaluated as
potassium channel modulators by measuring rhubidium ion release in
the following assay.
[0147] Methods: PC-12 cells were grown at 37.degree. C. and 5%
CO.sub.2 in DMEM/F12 Medium supplemented with 10% horse serum, 5%
fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, 100 U/ml
streptomycin. They were plated in poly-D-lysine-coated 96-well cell
culture microplates at a density of 40,000 cells/well and
differentiated with 100 ng/ml NGF-7s for 2-5 days. For the assay,
the medium was aspirated and the cells were washed once with 0.2 ml
in wash buffer (25 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM MgCl.sub.2,
0.8 mM NaH.sub.2PO.sub.4, 2 mM CaCl.sub.2). The cells were then
loaded with 0.2 ml Rb.sup.+ loading buffer (wash buffer plus 5.4 mM
RbCl.sub.2, 5 mM glucose) and incubated at 37.degree. C. for 2 h.
Attached cells were quickly washed three times with buffer (same as
Rb.sup.+ loading buffer, but containing 5.4 mM KCl instead of RbCl)
to remove extracellular Rb.sup.+. Immediately following the wash,
0.2 ml of depolarization buffer (wash buffer plus 15 mM KCl) with
or without compounds was added to the cells to activate efflux of
potassium ion channels. After incubation for 10 min at room
temperature, the supernatant was carefully removed and collected.
Cells were lysed by the addition of 0.2 ml of lysis buffer
(depolarization buffer plus 0.1% Triton X-100) and the cell lysates
were also collected. If collected samples were not immediately
analyzed for Rb.sup.+ contents by atomic absorption spectroscopy
(see below), they were stored at 4.degree. C. without any negative
effects on subsequent Rb+analysis.
[0148] The concentration of Rb.sup.+ in the supernatants
(Rb.sup.+.sub.Sup) and cell lysates (Rb.sup.+.sub.Lys) was
quantified using an ICR8000 flame atomic absorption spectrometer
(Aurora Biomed Inc., Vancouver, B.C.) under conditions defined by
the manufacturer. One 0.05 ml samples were processed automatically
from microtiter plates by dilution with an equal volume of Rb.sup.+
sample analysis buffer and injection into an air-acetylene flame.
The amount of Rb.sup.+ in the sample was measured by absorption at
780 nm using a hollow cathode lamp as light source and a PMT
detector. A calibration curve covering the range 0-5 mg/L Rb.sup.+
in sample analysis buffer was generated with each set of plates.
The percent Rb.sup.+ efflux (F) was defined by
F=[Rb.sup.+.sub.Sup/(Rb.sup.+.sub.Sup+Rb.sup.+.sub.Lys)].times.100%.
[0149] The effect (E) of a compound was defined by:
E=[(F.sub.c-F.sub.b)/(F.sub.s-F.sub.b)].times.100%
where the F.sub.c is the efflux in the presence of compound in
depolarization buffer, F.sub.b is the efflux in basal buffer, and
FS is the efflux in depolarization buffer, and F.sub.c is the
efflux in the presence of compound in depolarization buffer. The
effect (E) and compound concentration relationship was plotted to
calculate an EC.sub.50 value, a compound's concentration for 50% of
maximal Rb.sup.+ efflux. The results are shown below. Legend: A:
EC50 1 nM-50 nM; B: EC50=50 nM-100 nM; C: EC50=100 nM-200 nM; D:
EC50=200 nM-500 nM.
TABLE-US-00001 TABLE 1 ACTIVITIES OF EXEMPLARY COMPOUNDS ACTIV-
COMPOUND ITY ##STR00033## A ##STR00034## A ##STR00035## A
##STR00036## A ##STR00037## A ##STR00038## A ##STR00039## D
##STR00040## A ##STR00041## A ##STR00042## A ##STR00043## A
##STR00044## A ##STR00045## A ##STR00046## A ##STR00047## C
* * * * *